Topic
Transcriptional mechanisms regulating skeletal muscle differentiation
Phosphorylation and alternative splicing of MEF2C, a dual switch
function in muscle regeneration.
F. Baruffaldia, Sara Badodia, Luca De Feoa, Massimo Ganassib, Renata Battinia, C. Imbrianoa, Carmine Nicolettic, Antonio Musaròc, Margaret Buckingham, Didier
Montarrasd, S. Molinaria
a Dipartimento di Scienze della Vita and b Dipartimento di Scienze Biomediche, Metaboliche e Neuroscienze, Università di Modena e Reggio Emilia, Modena, Italy; c Institute
Pasteur-Cenci Bolognetti, DAHFMO-Unit of Histology and Medical Embryology, IIM, Sapienza University of Rome, 00161, Italy; d Department of Developmental and Stem Cell Biology,
CNRS URA 2578, Institut Pasteur, Paris, France.
Muscle regeneration is a multistep process that is regulated by a restricted number of transcription factors whose activity is modulated at multiple levels. However, how different layers of regulation are coordinated to promote adult myogenesis is not yet understood. Here we show that the MEF2C transcription factor controls multiple steps of muscle regeneration, including myogenic progression of satellite cells and muscle maturation of newly generated myofibers, exhibiting multiple functions that depend on alternative splicing and
post-translational modifications. Inclusion of the 1 exon in Mef2c transcripts is upregulated in proliferating mouse satellite cells and in the early phases of muscle regeneration. The encoded MEF2C1 isoform stimulates expansion of primary myoblasts ex vivo and in vivo. The pro-proliferative activity of MEF2C is mediated by phosphorylation of two phosphoserines located in exon 1. Subsequent terminal differentiation and growth of newly formed myofibers are promoted by dephosphorylated MEF2C1 and MEF2C2. Our results thus reveal an important role for regulatory interactions between alternative splicing and post translational modifications of a single transcription factor in the control of the multilayered regulatory programs required for adult myogenesis.